Acromegaly is a hormonal disorder that results when the pituitary gland produces excess growth hormone (GH). It most commonly affects middle-aged adults and can result in serious illness and premature death. Once diagnosed, acromegaly is treatable in most patients, but because of its slow and often insidious onset, it frequently is not diagnosed correctly. The most serious health consequences of acromegaly are diabetes mellitus, hypertension and increased risk of cardiovascular disease. Patients with acromegaly are also at increased risk for polyps of the colon that can develop into cancer. When GH-producing tumors occur in childhood, the disease that results is called gigantism rather than acromegaly. Fusion of the growth plates of the long bones occurs after puberty so that development of excessive GH production in adults does not result in increased height. Prolonged exposure to excess GH before fusion of the growth plates causes increased growth of the long bones and increased height.
Acromegaly is caused by prolonged overproduction of growth hormone (GH) by the pituitary gland. The pituitary is a small gland at the base of the brain that produces several important hormones to control body functions such as growth and development, reproduction, and metabolism. GH is part of a cascade of hormones that, as the name implies, regulates the physical growth of the body. This cascade begins in a part of the brain called the hypothalamus, which makes hormones that regulate the pituitary. One of these, GH-releasing hormone (GHRH), stimulates the pituitary gland to produce GH. Another hypothalamic hormone, somatostatin, inhibits GH production and release. Secretion of GH by the pituitary into the bloodstream causes the production of another hormone, called insulin-like growth factor 1 (IGF-1), in the liver. IGF-1 is the factor that causes the growth of bones and other tissues of the body. IGF-1, in turn, signals the pituitary to reduce GH production. GHRH, somatostatin, GH and IGF-1 levels in the body are tightly regulated by each other, and their levels are influenced by environmental stimuli such as sleep, exercise, stress, food intake and blood sugar levels. If the pituitary produces GH independent from the normal regulatory mechanisms, the level of IGF-1 would rise, leading to bone growth and organ enlargement. Excess GH also causes changes in sugar and lipid metabolism and can cause diabetes.
In over 90% of acromegaly patients, the overproduction of GH is caused by a benign tumor of the pituitary gland, called an adenoma. These tumors produce excess GH and, as they expand, compress surrounding brain tissues, such as the optic nerves. This expansion causes the headaches and visual disturbances that are often symptoms of acromegaly. In addition, compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and breast discharge in women and impotence in men.
In some patients, acromegaly is caused not by pituitary tumors but by tumors of the pancreas, lungs and adrenal glands. These tumors lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH, the hormone that stimulates the pituitary to make GH. In these patients, the excess GHRH can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect. When these non-pituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve.
Acromegaly treatment regimens include reducing GH production to normal levels to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, to preserve normal pituitary function, and to reverse or ameliorate the symptoms of acromegaly. Treatment options include surgical removal of the tumor, drug therapy and radiation therapy of the pituitary.
Octreotide has been demonstrated to be effective in the management of acromegaly. GH levels usually decrease within two hours following a subcutaneous octreotide injection. Octreotide results in a decrease in GH and IGF-1 levels in a majority of patients with normalization of IGF-1 levels in up to 60% of patients, indicating biochemical remission. Most patients note a marked improvement in their symptoms of acromegaly including headaches, joint pains and diaphoresis very soon after starting octreotide therapy. Octreotide is currently available as Sandostatin LAR® Depot, which is, upon reconstitution, a suspension of microspheres containing octreotide acetate. Sandostatin LAR® Depot is the only medication indicated for the long-term maintenance therapy in acromegalic patients. It is also indicated for the long-term treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and profuse water diarrhea associated with VIP-secreting tumors. Sandostatin LAR® Depot is administered via intramuscular injection every four weeks, following a titration period. Octreotide acetate has also been available in an immediate-release formulation, Sandostatin® Injection solution, which is required to be administered by injection three times daily. In patients who do not have a significant reduction in GH levels in response to intermittent octreotide injections, more frequent dosing of octreotide may result in a greater clinical response. Octreotide may be administered continuously by a subcutaneous pump to patients with refractory acromegaly to prevent escape of GH between injections.
In light of the efficacy of octreotide for treating acromegaly and lack of a controlled-release treatment method and formulation of octreotide, there is a need for a formulation and delivery method that can deliver octreotide over a period of time at a controlled rate to avoid the complications of a patient's having to suffer, for example, multiple periodic injections. There is also a clear need for a formulation and delivery method that can deliver octreotide over a period of time at a controlled rate to effectively treat other disorders and conditions, and/or their associated symptoms, including conditions and disorders characterized by or related to increased levels of GH and IGF-1.